Natural products are represented among clinically useful antitumor agents. The general goal of this project is to find and identify small molecules that can manipulate function of proteins and other receptors relevant to cancer. Answers to critical questions related to mechanism and site of action of cytotoxic compounds are now desired much earlier in the progression from compound discovery to clinical trial. Truly novel chemotherapeutic agents that are most likely to attract interest are cytotoxic or cytostatic compounds that exhibit activity against solid tumors and also target novel points of intervention in the sequence of events in oncogenesis. Natural products that induce apoptosis in transformed proliferating tumor cells may lead to tumor cell-specific suppressive agents that are useful as cancer chemotherapeutic drugs. Drug-induced apoptosis involves cell-cycle specific events mediated by a family of genes and gene products including p53 and Bcl-2 that may constitute a novel target for cancer chemotherapy. Apoptosis has important implications in the clinical outcome of cancer chemotherapy, not only for arresting tumor growth, but also for solid tumor regression by channeling the disposal of apoptotic tumor cells without problematic inflammatory responses. Pure cytotoxic and cytostatic natural products will be isolated from invertebrates collected from sites of unique marine biodiversity based on bioassay-guided purification. Active compounds will be prioritized based on activity against HCT-116 (colon tumor) and CCRF-CEM (T-cell leukemia), MCF-7 (breast), PC-3 (prostate), SK-MEL-5 (malignant melanoma), A549 (lung carcinoma), and HL-60 (promyelocytic) tumor cell lines. Prioritized cytotoxic compounds that also induce apoptosis in PC-3 and MCF-7 will be evaluated further by cell flow cytometry and drug profiling using DNA-microarray technology to determine the involvement of genes in cell-cycle arrest related to drug-induced apoptotic events. Promising new leads that emerge from this evaluation will be advanced to in vivo trials in animal models to ascertain their potential usefulness as leads in development of novel anticancer drugs active against human solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085602-02
Application #
6655589
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
2002-09-06
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$241,962
Indirect Cost
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Liu, Chaomin; Molinski, Tadeusz F (2011) Preparation of ?-amino acids by oxidative oxazoline-oxazinone rearrangement-hydrogenation (OOOH). Scope and limitations. Chem Asian J 6:2022-7
Molinski, Tadeusz F; Dalisay, Doralyn S; Lievens, Sarah L et al. (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69-85
Skepper, Colin K; Macmillan, John B; Zhou, Guang-Xiong et al. (2007) Chlorocyclopropane macrolides from the marine sponge Phorbas sp. assignment of the configurations of phorbasides A and B by quantitative CD. J Am Chem Soc 129:4150-1
Lievens, Sarah C; Molinski, Tadeusz F (2006) Progressive-convergent elucidation of stereochemistry in complex polyols. The absolute configuration of (-)-sagittamide A. J Am Chem Soc 128:11764-5
Lievens, Sarah C; Molinski, Tadeusz F (2005) Sagittamides A and B. Polyacetoxy long-chain acyl amino acids from a didemnid ascidian. Org Lett 7:2281-4
Masuno, Makoto N; Young, Douglas M; Hoepker, Alexander C et al. (2005) Addition of Cl2C: to (-)-O-menthyl acrylate under sonication-phase-transfer catalysis. Efficient synthesis of (+)- and (-)-(2-chlorocyclopropyl)methanol. J Org Chem 70:4162-5
Rogers, Evan W; Molinski, Tadeusz F (2005) A cytotoxic carotenoid from the marine sponge Prianos osiros. J Nat Prod 68:450-2
Liu, Chaomin; Masuno, Makoto N; Macmillan, John B et al. (2004) Enantioselective total synthesis of (+)-milnamide A and evidence of its autoxidation to (+)-milnamide D. Angew Chem Int Ed Engl 43:5951-4
Masuno, Makoto N; Pawlik, Joseph R; Molinski, Tadeusz F (2004) Phorbasterones A-D, cytotoxic nor-ring A steroids from the sponge Phorbas amaranthus. J Nat Prod 67:731-3
Lievens, Sarah C; Hope, Hakon; Molinski, Tadeusz F (2004) New 3-oxo-chol-4-en-24-oic acids from the marine soft coral Eleutherobia sp. J Nat Prod 67:2130-2

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